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      Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor

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          Abstract

          Background

          Previous studies showed that autoantibodies (M 2-AA) against the second extracellular loop of M 2 muscarinic receptor (M 2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M 2-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M 2 receptor binding characteristics in rats long-term stimulated with M 2-AA in vivo.

          Methods

          M 2-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M 2AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M 2 receptor binding characteristics were determined by radioactive ligand binding assay.

          Results

          After immunization for 12 months, compared with vehicle group, M 2AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M 2AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M 2 receptor maximum binding capacity (B max) of the M 2AChR-el2-immunized rats significantly decreased, while the M 2 receptor dissociation constant (K d) was increased.

          Conclusions

          Our study suggested that long-term stimulation with M 2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction. Mitochondrial damage and the down-regulation of M 2 receptor density and affinity may be involved in the process.

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          Most cited references 28

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          A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding

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            Mitochondrial membrane potential probes and the proton gradient: a practical usage guide.

            Fluorescent probes for monitoring mitochondrial membrane potential are frequently used for assessing mitochondrial function, particularly in the context of cell fate determination in biological and biomedical research. However, valid interpretation of results obtained with such probes requires careful consideration of numerous controls, as well as possible effects of non-protonic charges on dye behavior. In this context, we provide an overview of some of the important technical considerations, controls, and parallel complementary assays that can be employed to help ensure appropriate interpretation of results, thus providing a practical usage guide for monitoring mitochondrial membrane potentials with cationic probes. In total, this review will help illustrate both the strengths and potential pitfalls of common mitochondrial membrane potential dyes, and highlight best-usage approaches for their efficacious application in life sciences research.
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              From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future.

               C. Kawai (1999)
              A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell-mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune system-mediated mechanism. Beneficial effects of alpha1-adrenergic blocking agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating therapy.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 June 2015
                2015
                : 10
                : 6
                Affiliations
                [1 ]Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, P. R. China
                [2 ]The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100069, P. R. China
                [3 ]Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China
                [4 ]Department of Pathology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China
                [5 ]Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China
                [6 ]Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Capital Medical University, Beijing, 100069, P. R. China
                Harbin Medical University, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: HL. Performed the experiments: SZ ZH Jin Wang LW YW TL. Analyzed the data: Jin Wang Jie Wang. Wrote the paper: SZ ZH Jin Wang LW YW TL HL.

                PONE-D-14-46939
                10.1371/journal.pone.0129563
                4472961
                26086781

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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                Figures: 3, Tables: 2, Pages: 13
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                Funding
                This study was supported by grants from the 973 Program Earlier Research Project (2014CB560704) to Huirong Liu ( http://program.most.gov.cn); the National Natural Science Foundation Youth Project (81300694) to Suli Zhang ( http://www.nsfc.gov.cn/); the 2013 Specialized Research Fund for Doctoral Program of Higher Education (20131107120021) to Suli Zhang ( http://www.moe.gov.cn/); and grants from the Scientific Research Base Construction-Scientific and Technological Innovation Platform-Metabolic Disorders Related Cardiovascular Diseases Research Platform Construction (municipal level) (PXM2014_014226_000038; http://www.bjedu.gov.cn/publish/portal27/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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